The invention relates to targeted drug therapy in general, and to eosinophil targeting in particular.
Eosinophils are one type of granulocytic leukocyte (white blood cell) or granulocyte that normally appear in the peripheral blood at a concentration of about 1-3% of total leukocytes. Their presence in tissues is normally primarily restricted to the gastrointestinal mucosa. In various disease states, eosinophils appear in increased numbers in the peripheral blood and/or tissues, a condition termed eosinophilia and described in Rothenberg, Eosinophilia, N. Engl. J. Med. 338, 1592-1600 (1998). Eosinophil accumulation in tissues may cause potent pro-inflammatory effects in many diseases. Eosinophilia occurs in various diseases including allergic disorders such as allergic rhinitis, asthma, and eczema, chronic inflammatory disorders such as inflammatory bowel disease, and specific syndromes such as eosinophilic gastroenteritis, eosinophilic colitis, eosinophilic cellulitis and eosinophilic fasciitis, as well as parasitic infections and certain types of malignancies.
Numerous pharmaceutical agents, known to inhibit eosinophil function, are used to treat a variety of eosinophil-related diseases. However, none of these agents have a mechanism of action that is directed specifically to eosinophils. For example, glucocorticoids are the most common treatment for allergic disorders, but glucocorticoids are nonspecific for eosinophils in addition to being highly toxic. Another type of non-specific inhibition of eosinophil function is by administration of the non-specific adhesion molecule blockers such as very-late-antigen 4 (VLA-4) inhibitors. Interleukin-5 (IL-5), a chief eosinophil growth factor, is also under evaluation as a compound to target for the purpose of specifically inhibiting eosinophilia. In animal studies, blocking IL-5 by administering a humanized monoclonal antibody against IL-5 has been demonstrated to be highly effective in blocking eosinophil-mediated diseases such as asthma. Blocking IL-5 action would, therefore, likely reduce the symptoms of asthma. However, no clinically feasible small molecule inhibitors have been identified that inhibit IL-5. The only current approach to IL-5 targeting is by administering neutralizing antibody.
A therapeutic agent that could specifically target eosinophil function and trafficking would therefore be desirable. Such an agent could be used for treatment of the wide variety of eosinophil-mediated conditions that are known. For example, pediatric asthma is an eosinophil-mediated condition whose incidence is on the rise and is now the chief diagnosis responsible for pediatric hospital admissions. Alleviation of pediatric asthma by an eosinophil-targeting agent, along with the spectrum of other eosinophil-mediated conditions, would be of tremendous benefit.
The invention is directed to a method for intracellular targeting. A ligand for a cellular CCR-3 surface receptor is provided under conditions to form a ligand-receptor complex, and the ligand-receptor complex is internalized into the cell. The internalized complex may alter a cellular function, such as cell proliferation, cell viability, chemotaxis, activation, trafficking, and/or preventing subsequent ligand binding. The ligand may have a compound bound to it, such as a toxin, a drug, an enzyme and/or a radionuclide, and the compound may be activated intracellularly. The compound may be bound to the ligand in a variety of ways, such as covalently or noncovalently, or a protein compound may be generated as a fusion protein with said ligand. The ligand may be eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein (MCP)-2, MCP-3 and/or MCP-4. The cell may be an eosinophil, a basophil, a lymphocyte and/or a microglial cell.
The invention is also directed to a composition for treating an eosinophil-mediated disorder. The composition is a ligand for a CCR-3 eosinophil receptor containing a compound such as a leukotriene inhibitor and/or an apoptosis inducer in a pharmaceutically acceptable formulation. The composition may be used to treat eosinophil-mediated disorders such as allergies, asthma, eczema, eosinophilic cardiomyopathy, eosinophilic gastroenteritis, hypereosinophilic syndrome, graft versus host disease, chronic fibrosis, a parasitic inflammatory disorder, drug reaction, eosinophilic pneumonias, episodic angioedema with eosinophilia, inflammatory bowel disease, eosinophilic leukemia and/or food enteropathy. The compound may be a prodrug that is activated upon internalization into the eosinophil.
The invention is further directed to a method to prevent eosinophilia by providing a ligand for a CCR-3 receptor on an eosinophil under conditions to form a ligand-receptor complex and internalizing the complex into an eosinophil. The method may have a compound bound to the ligand, such as a toxin, a drug, an enzyme, a leukotriene inhibitor, and/or an apoptosis inducer, and may be activated upon internalization into the eosinophil.
The invention is still further directed to a method to treat or protect against a human immunodeficiency virus (HIV). A ligand for a CCR-3 cell surface receptor is provided in a pharmaceutically acceptable formulation and under conditions to form a ligand-CCR-3 complex. HIV binding to the CCR-3 is prevented by internalizing the ligand-CCR-3 complex.
The invention is additionally directed to a method for down-regulating a CCR-3 cell surface receptor. A ligand for the receptor is provided under ligand-binding conditions, the ligand is bound to the receptor and the ligand and receptor are internalized into the cell. The ligand may be a chemokine, a chemokine analog, a small molecule antagonist and/or a small molecule agonist and may have a compound bound to the ligand.
One advantage of the invention includes the ability to prevent systemic drug toxicity by administering an drug that is activated intracellularly. These and other advantages will be apparent in light of the following figures and detailed description.